WO2016040048A1 - Bio-capteur de créatinine et son procédé d'utilisation - Google Patents

Bio-capteur de créatinine et son procédé d'utilisation Download PDF

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Publication number
WO2016040048A1
WO2016040048A1 PCT/US2015/047895 US2015047895W WO2016040048A1 WO 2016040048 A1 WO2016040048 A1 WO 2016040048A1 US 2015047895 W US2015047895 W US 2015047895W WO 2016040048 A1 WO2016040048 A1 WO 2016040048A1
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WO
WIPO (PCT)
Prior art keywords
liquid sample
enzyme
creatinine
electrode
active electrode
Prior art date
Application number
PCT/US2015/047895
Other languages
English (en)
Inventor
Wei Zhang
Jingzhong Zhang
Original Assignee
Siemens Healthcare Diagnostics Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Siemens Healthcare Diagnostics Inc. filed Critical Siemens Healthcare Diagnostics Inc.
Priority to US15/509,067 priority Critical patent/US10000784B2/en
Priority to EP15839509.5A priority patent/EP3191825B1/fr
Priority to CA2971351A priority patent/CA2971351C/fr
Priority to DK15839509.5T priority patent/DK3191825T3/da
Publication of WO2016040048A1 publication Critical patent/WO2016040048A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/001—Enzyme electrodes
    • C12Q1/002—Electrode membranes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/28—Electrolytic cell components
    • G01N27/30—Electrodes, e.g. test electrodes; Half-cells
    • G01N27/333—Ion-selective electrodes or membranes
    • G01N27/3335—Ion-selective electrodes or membranes the membrane containing at least one organic component
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/001—Enzyme electrodes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/001—Enzyme electrodes
    • C12Q1/005—Enzyme electrodes involving specific analytes or enzymes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/403—Cells and electrode assemblies
    • G01N27/4035—Combination of a single ion-sensing electrode and a single reference electrode
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483—Physical analysis of biological material
    • G01N33/487—Physical analysis of biological material of liquid biological material
    • G01N33/49—Blood
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/70—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving creatine or creatinine

Definitions

  • This disclosure relates to creatinine biosensors and the uses thereof. More specifically, this disclosure describes potentiometric creatinine sensors which utilizes one or both of a type of enzyme capable of directly producing ammonium ions (NH 4 + ) as a consequence of coming into contact with a liquid sample and an internal fill solution with a low free ammonia ion concentration.
  • a type of enzyme capable of directly producing ammonium ions (NH 4 + ) as a consequence of coming into contact with a liquid sample and an internal fill solution with a low free ammonia ion concentration.
  • the presence of creatinine in a patient's blood may, for example, function as an indicator of the patient's renal health as creatinine is a byproduct of muscle metabolism.
  • creatinine levels in a patient's blood sample may be used to assess kidney health as well as how the effectiveness of medication(s).
  • Standard multi-enzyme amperometric creatinine biosensors produce and then measure an electrical current which flows between the biosensor and the blood sample the biosensor is immersed in. Once measured, the resulting current can be used to determine the concentration of creatinine in the blood sample.
  • the current is measured using an active electrode (also referred to as a working electrode) and an inactive electrode (which may also be referred to as a compensation electrode).
  • the electrical current is a byproduct of an enzymatic cascade reaction which begins when the active electrode is inserted into the blood sample.
  • the two enzymes are immobilized onto the surface of the inactive electrode: Creatine Amidohydrolase and Sarcosine Oxidase.
  • Creatine Amidohydrolase reacts with the Creatine already present in the blood prior to the insertion of the active electrode to produce Sacrosine and Urea
  • the Sarcosine Oxidase enzyme reacts with the Sarcosine as well as O 2 and H 2 O in the sample to produce Glycine, Formaldehyde and H 2 O 2 — which then results in the creation of an electrical current.
  • the creatinine concentration in the sample can be determined.
  • the cascade reaction associated with the inactive electrode may be expresses as follows:
  • Multi-enzyme amperometric creatinine biosensors have several drawbacks.
  • the inventive concepts disclosed herein are directed to a potentiometric biosensor comprising an active electrode, an inactive electrode, and an internal fill solution.
  • the active electrode comprising an internal fill solution and a first membrane, the first membrane separating the internal fill solution from a liquid sample when the active electrode is inserted into the liquid sample, the first membrane containing a first type of enzyme capable of directly producing ammonium ions (NH 4 + ) as a consequence of coming into contact with the liquid sample and being devoid of a second type of enzyme.
  • the active electrode comprising the internal fill solution and a second membrane, the second membrane separating the internal fill solution from the liquid sample when the inactive electrode is inserted into the liquid sample, the second membrane being devoid of enzymes capable of directly producing ammonium ions (NH 4 + ) as a consequence of coming into contact with the liquid sample.
  • the internal fill solution having a total ammonium ion concentration (which includes complexed ammonium and free ammonium) in the range of 1 to 10 mM and a free ammonia ion concentration of three or four orders of magnitude lower than the total ammonium ion concentration.
  • Figure 1 illustrates one embodiment of a potentiometric creatinine biosensor.
  • inventive concepts are not limited in their application to the details of construction and the arrangement of the components or steps or methodologies set forth in the following description or illustrated in the drawings.
  • inventive concepts disclosed herein are capable of other embodiments or of being practiced or carried out in various ways.
  • phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting the inventive concepts disclosed and claimed herein in any way.
  • compositions, processes, methods, articles, or apparatus that comprises a list of elements are not necessarily limited to only those elements but may include other elements not expressly listed or inherently present therein.
  • the terms “approximately,” “about,” “substantially” and variations thereof are intended to include not only the exact value qualified by the term, but to also include some slight deviations therefrom, such as deviations caused by measuring error, manufacturing tolerances, wear and tear on components or structures, settling or precipitation of cells or particles out of suspension or solution, chemical or biological degradation of solutions over time, stress exerted on structures, and combinations thereof, for example.
  • sample and variations thereof is intended to include biological tissues, biological fluids, chemical fluids, chemical substances, suspensions, solutions, slurries, mixtures, agglomerations, tinctures, slides, powders, or other preparations of biological tissues or fluids, synthetic analogs to biological tissues or fluids, bacterial cells (prokaryotic or eukaryotic), viruses, single-celled organisms, lysed biological cells, fixed biological cells, fixed biological tissues, cell cultures, tissue cultures, genetically engineered cells and tissues, genetically engineered organisms, and combinations thereof, for example.
  • bacterial cells prokaryotic or eukaryotic
  • viruses single-celled organisms
  • any reference to "one embodiment” or “an embodiment” means that a particular element, feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment.
  • the appearances of the phrase “in one embodiment” in various places in the specification are not necessarily all referring to the same embodiment.
  • inventive concepts disclosed herein are generally directed to potentiometric creatinine sensors which utilizes one or both of a type of enzyme capable of directly producing ammonium ions (NH 4 + ) as a consequence of coming into contact with a liquid sample and an internal fill solution with a low free ammonium ion concentration.
  • a type of enzyme capable of directly producing ammonium ions (NH 4 + ) as a consequence of coming into contact with a liquid sample and an internal fill solution with a low free ammonium ion concentration.
  • a type of enzyme capable of directly producing ammonium ions (NH 4 + ) as a consequence of coming into contact with a liquid sample and an internal fill solution with a low free ammonium ion concentration.
  • a type of enzyme capable of directly producing ammonium ions (NH 4 + ) as a consequence of coming into contact with a liquid sample and an internal fill solution with a low free ammonium ion concentration.
  • the inactive electrode 2 and the active electrode 4 may each include a respective body 6A, 6B, an internal electrode conductor element 8A, 8B, an internal fill solution 10A, 10B (which may also be referred to as an internal fill solution, an internal electrolyte solution, or a reference solution), and an ion sensitive membrane 12A, 12B.
  • the body 6A, 6B for each of inactive electrode 2 and an active electrode 4 may take a variety of shapes and sizes (such as, for example, cylindrical or rectangular) and be constructed out of a glass or any other material known to a person skilled in the art.
  • Each internal electrode conductor element 8A, 8B may be, for example, an electrically conductive wire which extends between a point within the body 6A, 6B of the respective inactive electrode 2 and active electrode 4 to an external measurement device 20 (for example a volt meter, which may be alone or in combination with another computing device).
  • an external measurement device 20 for example a volt meter, which may be alone or in combination with another computing device.
  • both the inactive electrode 2 and the active electrode 4 are ammonium (NH 4 + ) ion-selective electrodes.
  • Fig. 1 depicts but one illustrative configuration of potentiometric creatinine biosensor 100 and that inactive electrode 2 and active electrode 4 may be arranged differently with respect to one another.
  • the internal fill solution 10A, 10B may refer to a solution having a fixed, known composition and characteristics contained within each body 6A, 6B.
  • Internal fill solution 10A, 10B includes NH 4 + and one or both of a chelator and a buffer solution. When combined in the proper concentrations, the NH 4 + and a chelator result in an internal fill solution 10A, 10B with a low concentration of free ammonium ions as compared to the total concentration of ammonium ions (which includes complexed ammonium and free ammonium ions).
  • the internal fill solution maybe comprised of: NH 4 NO 3 + AgNO 3 + buffer solution— with respective concentrations of, for example, lOmM of NH 4 NO 3 ; 2.46mM of AgNO 3 ; and 20mM of the buffer solution.
  • the Ag in the above internal fill solution 10A, 10B is but one example of a chelator.
  • Other examples of chelators include Zn and Pt. The presence of a chelator in the internal fill solution 10A, 10B results in the following reaction:
  • buffer solution has an basic pH level, for example, between 9-1 1, the basic buffer solution will help the chelator (e.g., Ag, Zn, and Pt) more readily complex with the NH 4 + in the internal fill solution.
  • a basic buffer solution may result in the formation constant, Kf, for equation (1) being 10 7 .
  • the result is an internal fill solution 10A, 10B with a concentration of free ammonium ions of about O. lmM. Additionally, the remaining ammonium ions in the internal fill solution 10A, 10B act as a reservoir during the use of the device 100.
  • one or more of, for example,: (1) the ratio of NH 4 + and the chelator in the internal fill solution; (2) the type of chelators ) used; and (3) the pH value of the buffer solution can be adjusted to achieve a low concentration of free ammonium ions in the internal fill solution 10A, 10B.
  • the concentration of free ammonium ions in various embodiments of the internal fill solutions may be 3, 4, 5, 6, 7, or 8 orders of magnitude lower than the total concentration of ammonium ions in the internal fill solution.
  • the internal fill solution may have any of the following concentrations of total ammonium and free ammonium ions, respectively: 1 mM and ⁇ ; ImM and ⁇ ; lOmM and 10 ⁇ ; lOmM and ⁇ ⁇ ; and 10 mM and O. lmM.
  • device 100 may function with an internal fill solution 10A, 10B that has a low concentration of free ammonium ions but is devoid of one or both of the chelator or the buffer solution.
  • an internal fill solution 10A, 10B may have a short shelf life.
  • stability may be improved and shelf life of the device extended.
  • the ion sensitive membranes 12A, 12B may be made from, for example, PVC, glass, crystal, or any other type of material know to a person of ordinary skill in the art and have opposing surfaces 22A, 22B. Opposing surfaces 22A, 22B contact the internal fill solution 10A, 10B and sample liquid 18, respectively.
  • the ion sensitive membranes 12A, 12B are integrated into the body 6A, 6B of each respective electrode such that the internal fill solution 10A, 10B is prevented from contacting the liquid sample 18.
  • ion sensitive membranes 12A, 12B are ammonium ion-specific.
  • the ion sensitive membrane 12B of the active electrode 4 contains one or more ammonium ion (NH 4 + ) producing enzymes 14 (hereinafter 'enzyme(s) 4') immobilized onto the surface 22B of the ion sensitive membrane 12B and which produce ammonium ions (NH 4 + ) upon coming into contact with sample liquid 18.
  • Enzyme 14 may be any type of enzyme capable of reacting with creatinine in the liquid sample 18 in order to directly produce ammonium ions (NH 4 + ) as a direct consequence of coming into contact with liquid sample 18.
  • two types of enzyme 14 include creatinine iminohydrolase (CIH) and creatinine deimianase (CD). Other types of enzyme 14 may be understood to someone of ordinary skill in the art.
  • the ion sensitive membrane 12B of the active electrode 4 comprises a single type of enzyme 14 which produces ammonium ion (NH 4 + ) upon coming into contact with sample liquid 18 and is devoid of another type of enzyme which directly produces ammonium ion (NH 4 + ) upon coming into contact with sample liquid 18.
  • the ion sensitive membrane 12B of the active electrode 4 comprises two or more types of enzyme 14— each of which produces ammonium ion (NH 4 + ) upon coming into contact with sample liquid 18.
  • the ion sensitive membrane 12A of the inactive electrode 2 does not contain a substantial amount of enzyme 14.
  • active electrode 4 and inactive electrode 2 may contain other types of enzymes which do not react with creatinine in the liquid sample 18 in order to directly produce ammonium ions (NH 4 + ) in the liquid sample 18. Any enzymatic reaction which does not directly product ammonium ions (NH 4 + ) in the liquid sample 18 can be ignored during the computation of creatinine in the liquid sample 18.
  • potentiometric creatinine biosensor 100 An illustrative use of potentiometric creatinine biosensor 100 will now be described.
  • liquid sample 18 sample liquid 18 may be blood or urine
  • the immobilized enzyme 14 on the surface 22B of the ion sensitive membrane 12B catalyzes the hydrolysis of creatinine with water ( H 2 O) in the sample to produce, among other compounds, ammonium ions (NH 4 + ).
  • This reaction may be expressed as follows:
  • ammonium ions (NH 4 + ) created during this reaction are located in an area adjacent to surface 22B of ion sensitive membrane 12B and result in an increase in the electrical potential between opposing surfaces 22A, 22B of the ion sensitive membrane 12B as the number of ammonium ions (NH 4 + ) in the area of the sample liquid 18 adjacent to the ion sensitive membrane 12B increase as compared to the number of ammonium ions (NH 4 + ) in the internal fill solution 10B (which is held constant).
  • This electrical potential is picked up by internal electrode 8B and input into measuring instrument 20 as measurement signal 24. This electrical potential may be measured in, for example, mV.
  • sample liquid 18 such as blood will contain at least some amount of ammonium ions (NH 4 + ) prior to the insertion of the active electrode 4 and may interfere with measurement of creatinine in the sample liquid 18.
  • inactive electrode 2 is also inserted into the sample liquid 18. Inactive electrode 2 does not contain immobilized enzyme 14 on ion sensitive membrane 12A. As such, the inactive electrode 2 measures electrical potential caused by the different in ammonium ions (NH 4 + ) concentrations between the sample liquid 18 and the internal fill solution 10 across opposing surfaces 22A, 22B of the ion sensitive membrane 12A. This electrical potential is picked up by internal electrode 8A and input into measuring instrument 20 as compensation signal 26.
  • the measuring instrument 20 In order to identify the change in the electrical potential attributable to only the ammonium ions formed as a result of the reaction of creatinine in the sample liquid 18 with the immobilized enzyme 14, the measuring instrument 20, or a computing device connected to measuring instrument 20, subtracts the value of the compensation signal 26 from the value of measurement signal 24 and outputs the result. Alternatively, a user may use measuring instrument 20 to read compensation signal 26 and measurement signal 24 and manually subtract compensation signal 26 from measurement signal 24. Once computed, the resulting electrical potential value is proportional to the creatinine concentration in the sample liquid 18. Thus, the resulting current can be used to determine the concentration of creatinine in the sample liquid 18.
  • illustrative potentiometric creatinine biosensor 100 has a low limit of detection (LLOD) of

Abstract

La présente invention concerne des bio-capteurs de créatinine et leurs utilisations. Plus spécifiquement, la présente invention concerne des capteurs de créatinine potentiométriques qui utilisent l'un ou les deux d'un type d'enzyme capable de produire directement des ions ammonium (NH4+) suite à la mise en contact avec un échantillon de liquide et une solution de remplissage interne ayant une faible concentration d'ions ammonium libres.
PCT/US2015/047895 2014-09-08 2015-09-01 Bio-capteur de créatinine et son procédé d'utilisation WO2016040048A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US15/509,067 US10000784B2 (en) 2014-09-08 2015-09-01 Creatinine biosensor and method of using the same
EP15839509.5A EP3191825B1 (fr) 2014-09-08 2015-09-01 Bio-capteur de créatinine
CA2971351A CA2971351C (fr) 2014-09-08 2015-09-01 Bio-capteur de creatinine et son procede d'utilisation
DK15839509.5T DK3191825T3 (da) 2014-09-08 2015-09-01 Kreatininbiosensor

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201462047314P 2014-09-08 2014-09-08
US62/047,314 2014-09-08

Publications (1)

Publication Number Publication Date
WO2016040048A1 true WO2016040048A1 (fr) 2016-03-17

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Application Number Title Priority Date Filing Date
PCT/US2015/047895 WO2016040048A1 (fr) 2014-09-08 2015-09-01 Bio-capteur de créatinine et son procédé d'utilisation

Country Status (5)

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US (1) US10000784B2 (fr)
EP (1) EP3191825B1 (fr)
CA (1) CA2971351C (fr)
DK (1) DK3191825T3 (fr)
WO (1) WO2016040048A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3649505A (en) * 1969-03-03 1972-03-14 Beckman Instruments Inc Ammonia sensor
US3776819A (en) * 1969-12-22 1973-12-04 Monsanto Co Urea determination and electrode therefor
EP0068025B1 (fr) * 1980-11-17 1987-11-04 Shimadzu Corporation Electrode de reference
US20090045056A1 (en) * 2004-10-05 2009-02-19 Jason Berberich Stable three enzyme creatinine biosensor
US20130220820A1 (en) * 2001-05-31 2013-08-29 Prasad Pamidi Cross-linked enzyme matrix and uses thereof
US20140158536A1 (en) * 2012-11-13 2014-06-12 United Science Llc Sensor Apparatus

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5963554A (ja) * 1982-10-04 1984-04-11 Hitachi Ltd ウレア−ゼ固定化尿素電極およびその製造方法
TWI407099B (zh) * 2008-08-01 2013-09-01 私立中原大學 電壓式生物感測器及其製作方法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3649505A (en) * 1969-03-03 1972-03-14 Beckman Instruments Inc Ammonia sensor
US3776819A (en) * 1969-12-22 1973-12-04 Monsanto Co Urea determination and electrode therefor
EP0068025B1 (fr) * 1980-11-17 1987-11-04 Shimadzu Corporation Electrode de reference
US20130220820A1 (en) * 2001-05-31 2013-08-29 Prasad Pamidi Cross-linked enzyme matrix and uses thereof
US20090045056A1 (en) * 2004-10-05 2009-02-19 Jason Berberich Stable three enzyme creatinine biosensor
US20140158536A1 (en) * 2012-11-13 2014-06-12 United Science Llc Sensor Apparatus

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3191825A4 *

Also Published As

Publication number Publication date
US10000784B2 (en) 2018-06-19
EP3191825A1 (fr) 2017-07-19
CA2971351A1 (fr) 2016-03-17
US20170247736A1 (en) 2017-08-31
EP3191825A4 (fr) 2017-10-25
CA2971351C (fr) 2019-02-26
DK3191825T3 (da) 2019-05-06
EP3191825B1 (fr) 2019-02-27

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